Details
| Original language | English |
|---|---|
| Pages (from-to) | 17162-17190 |
| Number of pages | 29 |
| Journal | Journal of medicinal chemistry |
| Volume | 67 |
| Issue number | 19 |
| Early online date | 20 Sept 2024 |
| Publication status | Published - 10 Oct 2024 |
Abstract
Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched molecular pairs, l-amino acids were preferred over d-amino acids. A rigidification to a six-membered system stabilized the bioactive conformation for the on-target Escherichia coli gyrase, but did not improve antimicrobial activity. Compound CN-CC-861, carrying a propargyl side chain, had more than 16-fold lower minimal inhibitory concentration (MIC) values against Enterococcus faecalis, Staphylococci and Acinetobacter strains, compared to known analogues. Moreover, CN-CC-861 retained activity against multidrug-resistant enterococci, displayed strong bactericidal activity, moderate-low frequencies of resistance and in vivo efficacy in a neutropenic thigh infection model with E. coli. Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
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In: Journal of medicinal chemistry, Vol. 67, No. 19, 10.10.2024, p. 17162-17190.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Optimization of the Central α-Amino Acid in Cystobactamids to the Broad-Spectrum, Resistance-Breaking Antibiotic CN-CC-861
AU - Kohnhäuser, Daniel
AU - Seedorf, Tim
AU - Cirnski, Katarina
AU - Heimann, Dominik
AU - Coetzee, Janetta
AU - Sordello, Sylvie
AU - Richter, Jana
AU - Stappert, Moritz
AU - Sabuco, Jean Francois
AU - Corbett, David
AU - Bacque, Eric
AU - Rox, Katharina
AU - Herrmann, Jennifer
AU - Vassort, Aurelie
AU - Muller, Rolf
AU - Kirschning, Andreas
AU - Bronstrup, Mark
N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.
PY - 2024/10/10
Y1 - 2024/10/10
N2 - Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched molecular pairs, l-amino acids were preferred over d-amino acids. A rigidification to a six-membered system stabilized the bioactive conformation for the on-target Escherichia coli gyrase, but did not improve antimicrobial activity. Compound CN-CC-861, carrying a propargyl side chain, had more than 16-fold lower minimal inhibitory concentration (MIC) values against Enterococcus faecalis, Staphylococci and Acinetobacter strains, compared to known analogues. Moreover, CN-CC-861 retained activity against multidrug-resistant enterococci, displayed strong bactericidal activity, moderate-low frequencies of resistance and in vivo efficacy in a neutropenic thigh infection model with E. coli. Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.
AB - Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched molecular pairs, l-amino acids were preferred over d-amino acids. A rigidification to a six-membered system stabilized the bioactive conformation for the on-target Escherichia coli gyrase, but did not improve antimicrobial activity. Compound CN-CC-861, carrying a propargyl side chain, had more than 16-fold lower minimal inhibitory concentration (MIC) values against Enterococcus faecalis, Staphylococci and Acinetobacter strains, compared to known analogues. Moreover, CN-CC-861 retained activity against multidrug-resistant enterococci, displayed strong bactericidal activity, moderate-low frequencies of resistance and in vivo efficacy in a neutropenic thigh infection model with E. coli. Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.
UR - http://www.scopus.com/inward/record.url?scp=85204890450&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c00927
DO - 10.1021/acs.jmedchem.4c00927
M3 - Article
C2 - 39303218
AN - SCOPUS:85204890450
VL - 67
SP - 17162
EP - 17190
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
SN - 0022-2623
IS - 19
ER -